Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

The term HIV exposed seronegative (HESN) is used to describe individuals who remain uninfected despite multiple exposures to HIV. Our research program aims to understand why HESN are resistant to HIV infection, which is information that is potentially important for the design of preventive vaccines for HIV. Previously, we showed that Natural Killer (NK) cells are an important component of protective immunity to HIV in HESN. NK cells become activated rapidly upon encountering HIV infected cells and secrete anti-viral factors that can suppress HIV replication or kill HIV infected cells. They can do this directly or indirectly by antibody dependent cellular cytotoxicity (ADCC). In ADCC, NK cells are brought into close contact with the cells they kill via an antibody (Ab) bridge that links NK cells with HIV infected cells. In a group of subjects who were mostly injection drug user (IDU) HESN we found that genes for certain NK receptors (NKR) and NKR paired with the HLA ligands they recognize, were associated with protection from infection. NK cells from subject with protective gene combinations had higher anti-viral activity than those from individuals with control genotypes. We propose here to verify these results in sexually exposed HESN. We will study the mechanism used by NK cells to mediate their anti-viral effect. In the only modestly successful HIV vaccine trial conducted to date, induction of non neutralizing Abs, which may function through ADCC were found to correlate with protection from infection. We will investigate whether gene combinations that influence direct NK activity also influence the potency of NK activity mediated by ADCC. This research has relevance to the design of preventive vaccines for HIV.